We present the first spatial atlas linking microbiome niches (Streptococcus/Acetivibrio depletion) to CD8+ T-cell exhaustion via butyrate-HDAC-PD-1 axis, resolving a critical gap in understanding ICI resistance in CRC (Figure 7D), establishing the CMS score as a clinically actionable predictor of immunotherapy and targeted-agent resistance. Here, HDAC9 is linked to colorectal carcinoma.